Abstract
Osteonecrosis of the femoral head is a disease that leads to gradual degeneration of the hip joint causing immobility and a devastating impairment of quality of life. Early stage disease is characterised by a bone marrow edema of the proximal femur, a sight it shares with bone marrow edema syndrome. Although total hip arthroplasty offers quick symptom relief and functionally appealing results the treatment remains challenging, with its particularly young patients and considering limited non-invasive treatment options. We treated 6 patients with bone marrow edema in MRI and suspected osteonecrosis of the hip joint with calcium dobesilate, a vasoactive agent used in the treatment of diabetic retinopathy. We could demonstrate rapid symptom relief and concomitant disease remission on control MRI in early stage disease without any adverse events. Patients at advanced stages benefited in terms of pain reduction, but the treatment failed to halt disease progression. To the best of our knowledge, this is the first report of the therapeutic administration of calcium dobesilate in patients with bone marrow edema syndrome or osteonecrosis of the hip joint.
Keywords: Bone marrow edema syndrome, Osteonecrosis, Non-operative treatment, Calcium dobesilate
1. Introduction
Osteonecrosis of the femoral head (ONFH) is well-known pathology. The natural, untreated course of the disease often leads to progression with collapse of the femoral head causing immobility and a devastating impairment of the quality of life of the patients.1 There are several known risk factors, associated diseases and predisposing gene alterations. The most frequently quoted are corticosteroids and alcohol use.2 There is a male predominance and the patient population is particularly young (average age at treatment 33–38 years).3,4 The pathophysiology of osteonecrosis is poorly understood but is generally believed to be the result of an interrupted blood supply to the femoral head, leading to its degeneration. In histopathologic specimens the condition is characterised by a complex process of initial bone marrow and osteocyte necrosis followed by a reactive hyperaemia with a subsequent repair process of bone resorption and formation leading to a loss of structural integrity of the subchondral trabeculae. Cases with an obvious interruption of the vasculature suppling to the femoral head (i.e. fracture, dislocation or radiation) constitute the traumatic osteonecrosis. The exact pathogenesis of the non-traumatic osteonecrosis remains uncertain. For the remaining unclear cases two mechanisms have been proposed. Intervascular occlusion through thrombi or embolic fat and intraosseous extravascular obstruction through intraosseous pressure rise caused by an intraosseous edema or hypertrophic lipocytes.2,4,5
Bone marrow edema syndrome (BMES), a complex of groin pain and bone marrow edema in magnetic resonance imaging (MRI), is a disease that is largely congruent with the ONFH in terms of the suspected pathomechanism, epidemiology, clinical and MR findings, but has a significantly more favourable natural course. It is unclear whether BMES is an entity of its own or represents the early stage of ONFH.6
Calcium dobesilate (Doxium®, Vifor Pharma Management Ltd., Switzerland), a drug used for the oral treatment of microangiopathy in diabetic retinopathy and chronic venous disease, has been shown to reduce platelet aggregation, decrease capillary permeability and blood hyperviscosity while enhancing the endothelium-dependent vascular relaxation.7 Calcium dobesilate was shown to reduce the intramedullary subchondral pressure in a model of osteoarthritic joints in rabbits.8 Furthermore, calcium dobesilate showed promising effects in the treatment of navicular disease, a condition phenotypically similar to osteonecrosis, in horses.9 Calcium dobesilate is a well-tolerated substance and its safety has been demonstrated during its long-standing use in humans.10, 11, 12
Therefore, with this theory of impaired femoral blood supply in mind we used calcium dobesilate in 6 patients with suspected osteonecrosis of the hip joint and bone marrow edema in MRI. To the best of our knowledge, this is the first report of the therapeutic administration of calcium dobesilate in patients with osteonecrosis of the hip joint or bone marrow edema syndrome.
2. Patients and methods
This case series included all 6 patients who were treated for unilateral osteonecrosis of the femoral head at our institution between 2017 and 2019. All patients initially presented with severe groin pain with symptoms worsening upon weight bearing severely limiting mobility and daily activities. The diagnosis was confirmed in all cases by the presence of bone marrow edema in the proximal femur and/or specific findings on MRI. The disease stage was determined based on the ARCO (Association Research Circulation Osseous) classification for osteonecrosis of the femoral head. At the time of diagnosis, all patients were screened for possible risk factors. Table 1 provides an overview of the patients’ baseline characteristics. All patients were treated off-label with a course of 500 mg calcium dobesilate twice daily for one month, irrespective of disease stage. No additional medication was given. The dosage was based on the latest summary of product characteristics as approved by local authorities as well as the anecdotal experience of other users. Controls were performed six weeks and three months after treatment initiation and at irregular intervals as required. The disease onset was evaluated by physical examination, self-reported pain level, ambulatory limitations and control MRI.
Table 1.
Baseline characteristics at time of diagnosis.
| № | Age | Gender | Affected side | ARCO stadium | Risk factors | BMI (kg/m2) | Analgesic treatment |
|---|---|---|---|---|---|---|---|
| 1 | 52 | Male | Left | Stage I | None | 31 | none |
| 2 | 54 | Male | Right | Stage I | None | 22,1 | none |
| 3 | 72 | Female | right | Stage II | History of chemotherapya | 32,9 | none |
| 4 | 68 | male | right | Stage IV | pre-existing hip arthrosis | 24,4 | none |
| 5 | 63 | male | right | Stage I | None | 22,5 | none |
| 6 | 61 | male | right | Stage II | History of B-Cell lymphomab | 25,3 | none |
Cisplatin, Pemetrexed, Erlotinib, Vinorelbin and Docetaxel in adenocarcinoma of the lung.
No histologic evidence of B-Cell-lymphoma in the femoral head was found.
Prior to submission informed consent to publish the relevant information, including imaging was obtained from all patients.
3. Results/cases
The results of the treatment in each individual patient can be seen in Table 2. At the time of the first follow-up, 6 weeks after treatment initiation, all patients experienced a rapid reduction in their pain-levels. Three patients (№ 1,2 and 5) reported to be free of pain and without any limitations to their mobility. The same three patients showed no signs of residual edema in the femoral head on control MRI of the pelvis at three months as shown in Fig. 1. Nevertheless Patient № 2 had a slight unrounding of the femoral head, which indicates a limited disease progression during the treatment. So far in these patients, no recurrence has arisen.
Table 2.
Outcome after 6 weeks and 3 months.
| № | Follow-up at 6 weeks |
Follow-up at 3 months |
|||
|---|---|---|---|---|---|
| Pain-level | Mobility | Pain-level | Mobility | MRI | |
| 1 | free of pain | no limitations | free of pain | no limitations | Normal |
| 2 | free of pain | no limitations | free of pain | no limitations | slight unrounding of the femoral head, no edema visible |
| 3 | moderate | no limitations | Moderate | no limitations | subchondral femoral head fracture, no edema visible |
| 4 | moderate | severe limitations | Arthroplasty | ||
| 5 | free of pain | no limitations | free of pain | no limitations | normal |
| 6 | moderate | severe limitations | arthroplasty | ||
Fig. 1.
Coronal T2- (a,b) and T1-weighted (c,d) MR images initially (left column) and at 3-month follow-up (right column) from Patient № 1 (№ = Number).
However, patients № 4 and 6, despite experiencing a significant reduction in their pain level, suffered from progressive disease with increasing limitations to their daily activities. Both patients eventually required total hip arthroplasty.
Patient № 3 continued to have pain at a moderate, yet tolerable level, still allowing an age-appropriate level of activity. In the control MRI one year after treatment, a subchondral fracture in the weight-bearing area of the femoral head was visible, despite showing a complete remission of the femoral head edema. To date, no further actions have been needed.
No adverse reactions to the administration of calcium dobesilate were observed, nor were any reported by the patients.
4. Discussion
Our case series suggests that calcium dobesilate can be a safe and effective treatment for patients with ONFH or BMES. No treatment related adverse reactions that could be linked to the use of calcium dobesilat were observed and no such events were reported by the patients themselves. This is in line with existing observations in other applications.10, 11, 12
Calcium dobesilate effectively reduced the pain associated with their respective hips in all patients. Those patients achieving analgesia stayed free of pain, even long after the use of calcium dobesilate was discontinued, which suggests an effective treatment of the underlying pathology. The same patient population showed complete remission in MRI. These observations are consistent in our study, and this correlation between decreasing bone marrow edema and reported pain levels has been known for a long time.13 Even patient № 3, who had initially ARCO stage II disease and was never entirely free of pain, maintained complete remission in MRI one year after treatment.
Overall, these observations imply that the use of calcium dobesilate in early stage osteonecrosis consistently prevents disease progression and might shorten the course of bone marrow edema syndrome. Unsurprisingly, structural damage that existed prior to treatment or occurred during the treatment remained unchanged.
In more advanced cases, calcium dobesilate was not able to positively affect the course of the disease (cf. patient № 4). In patient № 6 we observed a rapid disease progression despite an early disease stage upon diagnosis and a good response to the treatment in terms of pain reduction. The same patient suffered from a B-Cell lymphoma; however, it remains unclear whether this affected the outcome. There was no evidence of B-Cell lymphoma in the femoral head specimen. In both cases, a hip arthroplasty was performed.14,15
The mean age of our patients (63 years) is significantly higher than the average age of ONFH or BMES patients which might cause an overlap with osteoarthritis.3,4,6,16 The clinical presentation and MRI findings of all three conditions, especially in early stages of ONFH and in BMES, can have a similar appearance, thus making a distinction between both entities difficult.17,18
The establishment of an osteonecrosis diagnosis in early stages remains difficult and some authors have suggested that a bone marrow edema in MRI may be an independent entity,19,20 although transformations of BMES into osteonecrosis and subsequent joint destruction are also described.21 The discussion of the relationship between BMES and ONFH continues until a fundamental understanding of the pathophysiology is available. Until then, BMES and early stage ONFH remain largely descriptive diagnoses, rather reflecting the describer's point of view. Nevertheless, we regard the use of calcium dobesilate to be a therapeutic option for both entities, as the proposed effect of calcium dobesilate, based on current concepts on their respective pathomechanisms, should work in both entities. Iloprost, a synthetic analogue of prostacyclin PGI2, is already being used for its vasodilatative and platelet inhibiting properties and is part of current guidelines addressing osteonecrosis of the femoral head.15 However, Calcium dobesilate offers an oral alternative to Iloprost with a safer risk profile and thus may become a more readily available pharmacological treatment of early stage osteonecrosis of the femoral head.10
This study has a short follow up, thus the long-term course after treatment with calcium dobesilate remains unclear. Furthermore, it lacks standardized recording of pain level and mobility impairment.
Due to the nature of this study, further conclusions cannot be drawn from this case series. Further research, in particular randomized controlled studies, are necessary to verify the effectiveness of this treatment in osteonecrosis or bone marrow edema syndrome.
Author statement
Christopher Butler Ransohoff: Study design, data acquisition, Formal analysis and interpretation of data, Writing - original draft, Writing - review & editing. Georg Matziolis: Writing - review & editing. Henk Eijer: Study design, Writing - review & editing.
Conflict of Interest
The authors have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
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